Parkinson's disease (PD) is the second most common neurodegenerative disorder among the elderly worldwide (Lees et al., 2009; Grayson, 2010; Shin et al., 2009). Although the etiology of PD remains largely unknown, overproduction of nitric oxide (NO) is considered as a causative factor for the loss of dopaminergic neurons (Kavya et al., 2006).
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a common neurotoxin widely used to produce PD models (Langston & Irwin, 1986). MPTP is converted into its active metabolite 1-methyl-4-phenylpyridinium ion (MPP+) by the monoamine oxidase B (MAO-B) in the inner mitochondrial membrane (Tipton & Singer, 1993). MPP+ stimulates the production of superoxide radical and activates nitric oxide synthase (NOS) to produce nitric oxide (NO) radical (Gonzalez-Polo et al., 2003; Gonzalez-Polo et al., 2004b). Superoxide radical not only inhibits mitochondrial complex I of the electron transport chain, but also reacts with NO radical to form peroxynitrite ion (ONOO−), the precursor of the tissue-damaging hydroxyl radical (Beckman et al., 1990). Thus, inhibition of NOS activity decreases the production of NO radicals and further attenuates MPTP/MPP+-induced neurotoxicity (Przedborski et al., 1996).
High levels of neuronal nitric oxide synthase (nNOS) are found in the nigrostriatal regions and basal ganglia of post-mortem PD brains and animals treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a PD-inducing neurotoxin (Muramatsu et al., 2003). On the other hand, transgenic mice that lack the nNOS gene are more resistant to MPTP than wild-type mice (Hantraye et al., 1996). Selective nNOS inhibitors produce neuroprotective effects against MPTP both in vitro and in vivo. These results suggest that nNOS inhibitors might have therapeutic potential in the treatment of PD (Kavya et al., 2006; Li et al., 2007; Li et al., 2006; Choi et al., 2009).
SU4312 (3-[4-(dimethylamino)benzylidenyl]indolin-2-one) is a cell-permeable, potent and selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, that has been designed as a candidate drug for cancer therapy (Sun et al., 1998). SU4312 competes with ATP for binding to VEGFR-2 and is able to completely block vascular endothelial growth factor (VEGF) signaling in a non-competitive manner (Sun et al., 1998). Previous studies have demonstrated that SU4312 specifically inhibits VEGF-dependent angiogenesis without damaging normal cells (Miki et al., 2010; Tran et al., 2007). SU4312 also significantly reduces the proliferation of multiple myeloma and leukemia tumor cells in vitro (McMillin et al., 2010). It is suggested that the anticancer activity of SU4312 is achieved through direct inhibition of the proliferation of cancer cells and indirect suppression of angiogenesis. Moreover, the recently discovered capabilities of SU4312 to block Aβ plaque-induced vessel formation in APP23 transgenic mice, and to direct inhibit Parkinson's disease (PD)-associated leucine rich repeat kinase 2 (LRRK2) autophosphorylation highlight its potential to be developed for the treatment of neurodegenerative disorders (Lee et al., 2010; Schultheiss et al., 2006)
SU5416 ((3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one) was originally designed as a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) for cancer therapy (Sun et al., 1998). It occupies the ATP binding site of VEGFR-2, and thereby abolishes vascular endothelial growth factor (VEGF) signaling (Sun et al., 1998). In the pre-clinical studies, SU5416 inhibits VEGF-dependent angiogenesis both in vitro and in vivo (Fong et al., 1999). As the first VEGFR-2 inhibitor evaluated in clinical trial, SU5416 is well tolerated even at the concentration of 145 mg/m2 in patients with advanced malignancies in phase I clinical study (Stopeck et al., 2002). It was found that SU5416 and 5-fluorouracil-leucovorin in combination showed better efficacy than standard 5-fluorouracil-leucovorin therapy in the pilot phase I/II study (Ye et al., 2006). Nevertheless, test on this drug was discontinued for there were no significant clinical benefits in a randomized phase III trial (Shawver et al., 2002). Notably, SU5416 could be rapidly distributed to all organs, and accumulated in orthotopically implanted central nerve system (CNS) tumor model and in patients with refractory pediatric CNS tumors, suggesting that SU5416 could be delivered to the CNS by passing through the blood-brain barrier (Kieran et al., 2009).
Sunitinib (SU11248, N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) is an oral, multiple receptor tyrosine kinases (RTKs) inhibitor that was approved in U.S. for the treatment of advanced or metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors (Rock et al., 2007; Adams & Leggas, 2007). Sunitinib occupies the ATP binding sites of RTKs including vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR), and thereby abolishes RTKs-mediated tumor angiogenesis and tumor cell proliferation (Blay, 2010). Clinical study has shown that daily oral administration of sunitinib lead to a plasma steady-state levels between 50 and 100 ng/ml (Desar et al., 2009). After oral administration, sunitinib could rapidly reach brain tissue (Patyna & Peng, 2006; van der Veldt et al., 2007). Moreover, sunitinib treatment has been shown safe and efficient in brain metastasis of renal cell carcinoma (Medioni et al., 2007). These results suggest that sunitinib is able to penetrate the blood brain barrier and may be used to treat central nerve system diseases (Addeo & Caraglia., 2011).
As a result of their physiological properties and proven safety for human consumption, it would be attractive for the indole-ketones or indolidones, such as SU4312, SU5416 and SU11248, to be used in preparation of drugs for the treatment of neurodegenerative diseases such as Parkinson's disease if they can be proven as NOS inhibitors. This disclosure hereby describes the uses of indole-ketones or indolidones as NOS inhibitors and drugs for treatment of neurodegenerative diseases.